Noroviruses (NoVs) are the major cause of acute viral gastroenteritis worldwide. Currently, no specific vaccines or antiviral therapies are available to treat NoV infections. Although illness during NoV infection is generally self-limiting in healthy individuals, higher morbidity and mortality rates have been reported among populations lacking effective immune function, especially immunocompromised individuals and children younger than 5 years of age. An effective treatment against NoV infection is of high necessity, especially with the increasing number of clinical cases among these subjects. Phage display-based human antibody gene libraries have been widely used to select antibodies against various microbial or cancer antigens for prophylactic strategies, taking advantage of the large capacity and diversity of phage display, as well as its convenience and straightforward screening approaches. In order to explore potential antiviral therapeutics for NoV infection, we have constructed a human antibody gene library using PBMCs from NoV-infected human subjects enrolled in a NoV-challenge study and obtained promising data towards identifying highly specific antibody clones. In this application, we will re-screen the established human antibody library and construct new libraries, using optimal conditions identified in our previous screening experiments, to increase the screen efficiency and antigenic coverage to discover potential cross-reactive neutralizing antibodies against various NoV genotypes that cause major epidemics and sporadic gastroenteritis. Selected antibodies are not only capable of binding to different NoV variants, but also blocking related histo-blood group antigens (HBGAs) involved in NoV binding, thus, potentially inhibiting NoV infection in humans. Furthermore, a panel of isolated human antibody clones will be favorable for thorough analysis of NoV antigen epitopes recognized by human antibodies, which cannot be fully understood by using animal-origin antibodies. Successfully isolated human antibodies against various NoV variants would be highly valuable for potential prophylactic strategies among vulnerable populations. Meanwhile, they will be extremely helpful in understanding NoV antigenic variation, in order to facilitate future NoV vaccine design.